EARLY QUANTITATIVE AND FUNCTIONAL DEFICIENCY OF NK1(-LIKE THYMOCYTES IN THE NOD MOUSE())

An immunoregulatory role has recently been attributed to the discrete subset of major histocompatibility complex class I-restricted NK1(+) m ature heat-stable antigen(-) (HSA(-)) thymocytes expressing an unusual V beta 8-biased T cell receptor repertoire. NK1(+) T cells are the ma in interleukin (IL)-4 producers upon priming. We have studied the size and the function of this subset in the nonobese diabetic (NOD) mouse, a model of spontaneous T cell-mediated autoimmune insulin-dependent d iabetes. This study was complicated by the absence in this strain of t he NK1.1 allele, the only one for which an antibody is available. To c ircumvent this difficulty the cells, hereafter designated the NK1(+)-l ike T subset, were characterized by the use of monoclonal antibodies w hich showed the V beta 8 bias in the CD44(+) Ly-49(+) MEL-14(-) 3G11(- ) thymocyte subset of nonautoimmune strains and of its absence in clas s I-deficient (beta 2-microglobulin(-/-)) mice. A clear deficit in the number of NK1(+)-like cells was evidenced at 3 weeks of age in NOD mi ce. It was still present at 8 weeks of age in the double-negative CD4( -)CD8(-) population. The functional anomaly was even more striking: NO D mouse NK1(+)-like thymocytes virtually lacked the ability to produce IL-4 at 3 weeks and still showed a very reduced capacity at 8 weeks. NK1(+) T cell deficiency was also suggested in the periphery by the re duction of Ly-49A(+) cells in the spleen of 3- and 8-week-old NOD mice and the absence of short-term production of IL-4 in vitro by NOD mous e spleen cells 90 min after the administration of anti-CD3 antibody, a response attributed to NK1(+) T cells. Taken together, these data dem onstrate a very early defect in NK1(+)-like T cells which could be inv olved in the genesis of autoimmunity in NOD mice through a deficiency in Th2 cell function.